Rutaecarpine ameliorated sepsis-induced peritoneal resident macrophages apoptosis and inflammation responses
Rutaecarpine ameliorated sepsis-induced peritoneal resident macrophages apoptosis and inflammation responses
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DOI：
10.1016/j.lfs.2019.01.038
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发表时间：
2019-07-01
期刊：
影响因子：
6.1
通讯作者：
Yang, Bingchang
中科院分区：
文献类型：
--
作者：
Li, Zhiling;Yang, Mingshi;Yang, Bingchang
背景：脓毒症是一种危及生命的器官功能障碍疾病，由宿主对感染的反应失调引起。吴茱萸碱是吴茱萸的重要生物碱成分。目前还没有关于吴茱萸碱治疗脓毒症的效果的研究。方法：将小鼠随机分为四组：假手术组、脓毒症组、脓毒症加媒介物组和脓毒症加吴茱萸碱组。对脓毒症小鼠进行 CLP 手术。 CLP后1小时腹膜内注射芸香碱或媒介物。观察肝脏损伤、细菌感染、存活率和体重减轻情况，并通过流式细胞仪和免疫荧光显微镜分析腹腔常驻巨噬细胞比例的变化。 Western blotting检测NF-κB信号通路、内质网应激和凋亡相关蛋白的水平。 TUNEL法和Annexin V/PI法分别检测肝组织和腹腔巨噬细胞的凋亡。采用ELISA和qRT-PCR检测炎症因子。结果：吴茱萸碱可减轻体重减轻、细菌感染和肝损伤，调节炎症稳态，提高脓毒症所致的生存率。脓毒症小鼠腹腔巨噬细胞（CD11b(+)F4/80 (MHCIIlow)-M-hi）数量显着减少，这是由于内质网应激通过caspase-12信号通路诱导细胞凋亡所致。吴茱萸碱恢复了腹膜常驻巨噬细胞的比例以及CD11b(+)腹膜巨噬细胞中GATA6的水平。吴茱萸碱还可以通过抑制内质网应激/NF-kappa B通路的激活来减轻脓毒症引起的炎症反应。结论：吴茱萸碱通过抑制内质网应激介导的caspase-12和NF-kappa B通路，改善脓毒症引起的腹膜常驻巨噬细胞凋亡和炎症反应。我们的研究为治疗脓毒症的药物开发提供了新的见解。
Background: Sepsis is a life-threatening organ dysfunction disease caused by a dysregulated host response to infection. Rutaecarpine is an important alkaloid component of Evodia rutaecarpa. There has been no study on the therapeutic effects of rutaecarpine in sepsis.Methods: Mice were randomly assigned into four groups: sham, sepsis, sepsis plus vehicle and sepsis plus rutaecarpine groups. Mice in sepsis were administered CLP surgery. Rutaecarpine or vehicle was injected intraperitoneally 1 h after CLP. The liver damage, bacterial infection, survival rate and weight loss were observed, and changes in the ratio of peritoneal resident macrophages were analyzed by flow cytometry and immunofluorescence microscopy. Western blotting was used to identify the levels of NF-kappa B signaling pathway, ER stress and apoptosis related proteins. TUNEL and Annexin V/PI assay were used to detect the apoptosis of liver tissues and peritoneal resident macrophages, respectively. ELISA and qRT-PCR were used to detect the inflammatory factors.Results: Rutaecarpine alleviated weight loss, bacterial infection and liver injury, and regulated inflammation homeostasis, enhancing survival rate induced by sepsis. Population of peritoneal resident macrophages (CD11b(+)F4/80 (MHCIIlow)-M-hi)was significantly decreased in sepsis mice, which was resulted from ER stress-induced apoptosis through caspase-12 signaling pathway. Rutaecarpine restored the ratio of peritoneal resident macrophages and the level of GATA6 in CD11b(+) peritoneal macrophages. Rutaecarpine could also attenuate sepsis-induced inflammatory responses through inhibiting the activation of ER stress/NF-kappa B pathway.Conclusion: Rutaecarpine ameliorated sepsis-induced peritoneal resident macrophages apoptosis and inflammation responses through inhibition of ER stress-mediated caspase-12 and NF-kappa B pathways. Our study provided new insights for drug development against sepsis.